Drugs for treating respiratory and nasal disorders are frequently administered in aerosol formulations through the mouth or nose. One widely used method for dispensing such aerosol drug formulations involves preparing a suspension or solution formulation of the drug as a finely divided powder in a liquefied gas known as a propellant. The suspension is stored in a sealed container (or canister) capable of withstanding the pressure required to maintain the propellant as a liquid. The formulation may then be dispersed by activating a dose-metering valve affixed to the container.
The metering valve is typically designed to consistently release a fixed, predetermined mass of the aerosol drug formulation upon each activation. As the formulation is forced from the container through the dose-metering valve by the high vapor pressure of the propellant, the propellant rapidly vaporizes leaving a fast moving cloud of very fine particles of the drug formulation. This cloud of particles is directed into the nose or mouth of the patient by a channeling device such as a cylinder or open ended cone. Concurrently with the activation of the aerosol dose metering valve, the patient inhales the drug particles into the lungs or nasal cavity. Systems of dispensing drugs in this manner are known as “metered dose inhalers” (MDI's).
Patients often rely on medication delivered by MDI's for rapid treatment of respiratory disorders which are debilitating and in some cases, even life threatening, including for example asthma and chronic obstructive pulmonary disease (COPD). Pharmaceutical compounds for treatment of other conditions or illnesses are targeted for delivery with MDI technology. Therefore, it is essential that the prescribed dose of aerosol medication delivered to the patient consistently meet the specifications claimed by the manufacturer and comply with the requirements of the United States Food & Drug Administration (FDA) and other regulatory authorities. That is, every dose in the canister must be the same within close tolerances.
In some instances, the aerosol drug formulation may tend to adhere to and/or chemically react with the inner surfaces of the MDI, including the canister, metering valve and cap which all make up the MDI system. This can lead to the patient receiving significantly less than the prescribed amount of drug upon each activation of the MDI. Thus, it is often desirable to coat the inner surfaces of the metered dose inhaler, including the metering valve and the inner surface of the container, with a coating material that prevents the drug formulation from adhering to or reacting with the inner surfaces of the MDI.
Previously, fluorine-containing polymers, which have been known for decades to be useful as protective coatings for various articles have more recently been used as protective materials and to coat the inner surfaces of aluminum and aluminum alloy canisters intended for use in storing and administering pulmonary medicament, as described for example in U.S. Pat. No. 6,596,260 to Brugger et al., and in U.S. Pat. Nos. 6,546,928 and 6,532,955 to Ashurst et al., the subject matter of each of which is herein incorporated by reference in its entirety. The use of these fluorine-containing materials to protect the inner surfaces of the containers used to store the drug formulations also allows alternative propellant systems to be used, while at the same time preventing the contamination of the drug formulation with, for example, aluminum or compounds thereof.
However, in some instances, these fluorocarbon polymers may be solvent based rather than aqueous based. Many prior art coating formulations contain solvents that are capable of dissolving the polymer material to make it sprayable. Such prior art solvents include aromatic organic compounds such as n-methyl pyrrolidone, methyl isobutyl ketone, xylene, and/or toluene all of which are suspected carcinogens, among others. In addition, solvent-based cleaning solutions have typically been used to prepare the surfaces to allow coating thereon.
As such, it is also desirable to reduce the quantity of extractable organic compounds used in coating processes (such as solvents) which may contaminate the contents of the container. The use of organic solvents that are flammable has a further drawback in that the equipment used for coating needs to be appropriately protected against fire or explosion hazards. Also, these coatings require the addition of an adhesive to the polymer, otherwise the coating does not adhere sufficiently to the surface. Such adhesives may be costly and time consuming to apply or formulate, and may also be a source of drug contamination.
It is most desirable that any coatings applied to the interior surfaces of the containers, which will necessarily come into contact with the pharmacological formulation, have low available extractable organic compounds, such that there is no interaction between the coating formulation and the pharmacological formulation.
An improved process has been developed for coating metered dose inhaler canisters, including aluminum alloy, deep-drawn metered dose inhaler canisters, using a unique water-based cleaning composition in conjunction with a water-based crosslinked epoxy acrylate or other polymeric internal surface coating material as described herein. This invention has been developed to make the cleaning and coating technology consistent with present environmental regulations and workplace safety requirements, including control of emissions of volatile organic compounds (VOCs). Further, this invention has been developed to reduce the concentration of extractible organic compounds to the lowest practical level.
Prior to the process described herein, the majority of MDI canisters have been solvent-cleaned with a proprietary commercially supplied mixture of hydrocarbons and emulsifiers. While these remove most of the hydrocarbon lubricants used for deep drawing, the resulting surface contains residual oils and fatty acids that prevent wetting with water-based coatings. Prior to coating MDI cans cleaned in this way, they are typically heated above 200° C. to ‘burn off’ residual hydrocarbons. The remaining surface, however, is not fully wettable with water-based coating materials. Whereas the coating materials described herein might be applied to a surface treated in this manner, optimum adhesion and reduction of residual organic compounds is not assured. A hydrocarbon-free cleaning process was developed to greatly increase the surface wettability of the MDI canister while eliminating downstream contamination from residual hydrocarbons. Examples of a prior art cleaning solvents include Silksol and other types of emulsifiable and semi-emulsifiable hydrocarbon solvent cleaning systems. These typically may contain an aliphatic hydrocarbon solvent, similar to kerosene, and one or more surfactants to promote emulsification with water.
Accordingly, it is an object of the present invention to solve the problems associated with the prior art. It is also an object of the present invention to provide an improved process for coating an internal surface of a medicine storage container with a fluorine-containing polymer, to provide a finer, more uniform and unblemished coating with improved protective properties that requires no adhesive or primer, and which contains a minimum of extractable organic compounds. It is also an object of the present invention to provide a process for coating containers using an aqueous polymer suspension and to overcome the difficulties associated with producing good coatings from an aqueous suspension without using traditional volatile organic hydrocarbon solvents.